Glucarpidase

Glucarpidase
Black Box Warning
Adult Indications & Dosage
Pediatric Indications & Dosage
Contraindications
Warnings & Precautions
Adverse Reactions
Drug Interactions
Use in Specific Populations
Administration & Monitoring
Overdosage
Pharmacology
Clinical Studies
How Supplied
Images
Patient Counseling Information
Precautions with Alcohol
Brand Names
Look-Alike Names

Editor-In-Chief: C. Michael Gibson, M.S., M.D. [1];

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Black Box Warning

Title See full prescribing information for complete Boxed Warning. ConditionName: Content

Overview

Glucarpidase is a that is FDA approved for the {{{indicationType}}} of toxic plasma methotrexate concentrations (>1 micromole per liter) in patients with delayed methotrexate clearance due to impaired renal function.. There is a Black Box Warning for this drug as shown here. Common adverse reactions include .

Adult Indications and Dosage

FDA-Labeled Indications and Dosage (Adult)

• VORAXAZE (glucarpidase) is indicated for the treatment of toxic plasma methotrexate concentrations (>1 micromole per liter) in patients with delayed methotrexate clearance due to impaired renal function.

Limitation of Use

• VORAXAZE is not indicated for use in patients who exhibit the expected clearance of methotrexate (plasma methotrexate concentrations within 2 standard deviations of the mean methotrexate excretion curve specific for the dose of methotrexate administered) or those with normal or mildly impaired renal function because of the potential risk of subtherapeutic exposure to methotrexate.

Recommended Dose

• Administer VORAXAZE as a single intravenous injection of 50 Units per kg.

Administration

• Administer VORAXAZE intravenously as a bolus injection over 5 minutes. Flush intravenous line before and after administration of VORAXAZE.

Preparation

• Reconstitute the contents of the vial with 1 mL of sterile saline for injection, USP.
• Roll and tilt the vial gently to mix. Do not shake.
• Inspect the vial and discard VORAXAZE if the solution is not clear, colorless, and free of particulate matter.
• Use reconstituted VORAXAZE immediately or store under refrigeration at 36° to 46°F (2° to 8°C) for up to 4 hours if not used immediately. VORAXAZE contains no preservative and is supplied as a single-use vial. *Discard any unused product.

Off-Label Use and Dosage (Adult)

Guideline-Supported Use

There is limited information regarding Off-Label Guideline-Supported Use of Glucarpidase in adult patients.

Non–Guideline-Supported Use

There is limited information regarding Off-Label Non–Guideline-Supported Use of Glucarpidase in adult patients.

Pediatric Indications and Dosage

FDA-Labeled Indications and Dosage (Pediatric)

There is limited information regarding FDA-Labeled Use of Glucarpidase in pediatric patients.

Off-Label Use and Dosage (Pediatric)

Guideline-Supported Use

There is limited information regarding Off-Label Guideline-Supported Use of Glucarpidase in pediatric patients.

Non–Guideline-Supported Use

There is limited information regarding Off-Label Non–Guideline-Supported Use of Glucarpidase in pediatric patients.

Contraindications

• None

Warnings

Title See full prescribing information for complete Boxed Warning. ConditionName: Content

Serious Allergic Reactions

• Serious allergic reactions occurred in less than 1% of patients .

Monitoring Methotrexate Concentration/Interference with Assay

• Methotrexate concentrations within 48 hours following administration of VORAXAZE can only be reliably measured by a chromatographic method. DAMPA (4-deoxy-4-amino-N10-methylpteroic acid) is an inactive metabolite of methotrexate resulting from treatment with VORAXAZE. DAMPA interferes with the measurement of methotrexate concentration using immunoassays resulting in an erroneous measurement which overestimates the methotrexate concentration. Due to the long half-life of DAMPA (t1/2 of approximately 9 hours), measurement of methotrexate using immunoassays is unreliable for samples collected within 48 hours following VORAXAZE administration [see Clinical Pharmacology (12.1)].

Continuation and Timing of Leucovorin Rescue

• Continue to administer leucovorin after VORAXAZE. Do not administer leucovorin within 2 hours before or after a dose of VORAXAZE because leucovorin is a substrate for VORAXAZE .

• For the first 48 hours after VORAXAZE, administer the same leucovorin dose as given prior to VORAXAZE [see Warnings and Precautions (5.2)]. Beyond 48 hours after VORAXAZE, administer leucovorin based on the measured methotrexate concentration. Do not discontinue therapy with leucovorin based on the determination of a single methotrexate concentration below the leucovorin treatment threshold. Therapy with leucovorin should be continued until the methotrexate concentration has been maintained below the leucovorin treatment threshold for a minimum of 3 days.

• Continue hydration and alkalinization of the urine as indicated.

Adverse Reactions

Clinical Trials Experience

• Serious allergic reactions, including anaphylactic reactions, may occur. The most common adverse reactions (incidence >1%) with VORAXAZE are paraesthesias, flushing, nausea and/or vomiting, hypotension, and headache.

Clinical Trials Experience

• Because clinical trials are conducted under controlled but widely varying conditions, adverse reaction rates observed in clinical trials of VORAXAZE cannot be directly compared to rates in the clinical trials of other drugs and may not reflect the rates observed in practice.

• The evaluation of adverse reactions in patients treated with VORAXAZE is confounded by the population in which it was studied, patients with toxic plasma methotrexate levels due to impaired renal function. Adverse reactions related to toxic methotrexate levels due to prolonged methotrexate clearance include myelosuppression, mucositis, acute hepatitis, and renal dysfunction and failure.

• The safety of VORAXAZE is based on data from 290 patients who were treated in 2 single-arm, open-label, multicenter trials enrolling patients who had markedly delayed methotrexate clearance secondary to renal dysfunction. Patients with osteosarcoma were eligible for these studies if the plasma methotrexate concentration was greater than 50 μmol/L at 24 hours, greater that 5 μmol/L at 48 hours, or greater than 2 standard deviations above the mean methotrexate elimination curve at least 12 hours after methotrexate administration and there was a 2-fold or greater increase in serum creatinine above baseline. All other patients were eligible for these studies if the plasma methotrexate level was greater than 10 μmol/L more than 42 hours after the start of the methotrexate or the plasma level was greater than 2 standard deviations above the mean methotrexate excretion curve at least 12 hours following methotrexate and the serum creatinine was greater than 1.5 times the upper limit of normal or the creatinine clearance was less than 60 mL/min at least 12 hours following methotrexate administration.

• Study 1, conducted by the National Cancer Institute (NCI), enrolled 184 patients; safety information is available for 149 patients. VORAXAZE was given at a dose of 50 Units/kg as an intravenous injection over 5 minutes. Patients with pre-VORAXAZE methotrexate concentrations >100 μmol/L were to receive a second dose of VORAXAZE 48 hours after the first dose. The protocol specified that patients continue receiving intravenous hydration, urinary alkalinization and leucovorin, and that leucovorin administration be adjusted to ensure that it was not administered within two hours before or after VORAXAZE.

• In Study 1, VORAXAZE-related adverse reactions were collected on a flow sheet with a daily log of adverse reactions characterized as "glucarpidase toxicity." Additional safety information was collected from clinical records submitted by treating physicians. This information was abstracted and categorized using the National Cancer Institute (NCI) "Common Terminology Criteria for Adverse Events" (CTCAE) version 3 scale.

• The Study 1 population enrolled patients with a median age of 18 years (1 month to 85 years); 63% were male, and the underlying malignancies were osteosarcoma/sarcomas in 32%, and leukemia or lymphoma in 63% of patients. One (n=106) or 2 (n= 30) doses of VORAXAZE were administered intravenously; the number of doses was not specified in 13 patients. Doses ranged from 18 to 98 Units/kg, with a median dose of 49 Units/kg.

• Study 2 is an ongoing expanded access program. At the time of data cut-off, 243 patients were enrolled and safety data was available for 141 patients. VORAXAZE was given at a dose of 50 Units/kg as an intravenous injection over 5 minutes. The criterion for allowing patients to receive a second glucarpidase dose was not specified in the protocol. The protocol specified that patients continue receiving intravenous hydration, urinary alkalinization and leucovorin, and that leucovorin administration be adjusted to ensure that it was not administered within two hours before or after VORAXAZE.

• Study 2 enrolled patients with a median age of 17 years (6 months to 85 years); 64% were male, and the underlying malignancies were osteogenic sarcoma in 32%, and leukemia or lymphoma in 62% of patients. One (n=122) or 2 (n= 18) doses of VORAXAZE were administered intravenously; the number of doses was not specified for 1 patient. Doses ranged from 6 to 189 Units/kg, with a median dose of 50 Units/kg.

• In Study 2 only VORAXAZE-related adverse reactions were collected and severity was graded according to NCI CTCAE version 3.

• Among the 290 patients included in the safety evaluation of VORAXAZE, there were 8 deaths within 30 days of VORAXAZE exposure that were not related to progressive disease. Twenty-one of 290 patients (7%) experienced adverse reactions that were assessed as related to VORAXAZE. Most were Grade 1 or 2 events. One patient experienced related Grade 3 flushing. The most common related adverse reactions that were not hematologic, hepatic or renal events were paresthesia, flushing, and nausea and/or vomiting, which each occurred in 2% of patients (Table 1).

TABLE02

Immunogenicity

• As with all therapeutic proteins, there is potential for immunogenicity. In clinical trials, 121 patients who received one (n=99), two (n=21), or three (n=1) doses of VORAXAZE were evaluated for anti-glucarpidase antibodies. Twenty-five of these 121 patients (21%) had detectable anti-glucarpidase antibodies following VORAXAZE administration, of which 19 received a single dose of VORAXAZE and 6 received two doses of VORAXAZE. Antibody titers were determined using a bridging enzyme-linked immunosorbent assay (ELISA) for anti-glucarpidase antibodies.

• Neutralizing antibodies were detected in 11 of the 25 patients who tested positive for anti-glucarpidase binding antibodies. Eight of these 11 patients had received a single dose of VORAXAZE. However, the development of neutralizing antibodies may be underreported due to lack of assay sensitivity.

• The detection of antibody formation is highly dependent on the sensitivity and specificity of the assay. Additionally, the observed incidence of antibody (including neutralizing antibody) positivity in an assay may be influenced by several factors , including assay methodology, sample handling, timing of sample collection, concomitant medications, and underlying disease. For these reasons, comparison of incidence of antibodies to VORAXAZE with the incidence of antibodies to other products may be misleading.

Postmarketing Experience

There is limited information regarding Postmarketing Experience of Glucarpidase in the drug label.

Drug Interactions

• Use of VORAXAZE with Leucovorin

Leucovorin is a substrate for VORAXAZE. Do not administer leucovorin within 2 hours before or after a dose of VORAXAZE. No dose adjustment is recommended for the continuing leucovorin regimen because the leucovorin dose is based on the patient’s pre-VORAXAZE methotrexate concentration [see Warnings and Precautions (5.3) and Clinical Pharmacology (12.3)].

7.2 Other Substrate Interference

Other potential exogenous substrates of VORAXAZE may include reduced folates and folate antimetabolites.

Use in Specific Populations

Pregnancy

Pregnancy Category (FDA):

• Pregnancy Category

Pregnancy Category (AUS):

• Australian Drug Evaluation Committee (ADEC) Pregnancy Category

There is no Australian Drug Evaluation Committee (ADEC) guidance on usage of Glucarpidase in women who are pregnant.

Labor and Delivery

There is no FDA guidance on use of Glucarpidase during labor and delivery.

Nursing Mothers

There is no FDA guidance on the use of Glucarpidase with respect to nursing mothers.

Pediatric Use

There is no FDA guidance on the use of Glucarpidase with respect to pediatric patients.

Geriatic Use

There is no FDA guidance on the use of Glucarpidase with respect to geriatric patients.

Gender

There is no FDA guidance on the use of Glucarpidase with respect to specific gender populations.

Race

There is no FDA guidance on the use of Glucarpidase with respect to specific racial populations.

Renal Impairment

There is no FDA guidance on the use of Glucarpidase in patients with renal impairment.

Hepatic Impairment

There is no FDA guidance on the use of Glucarpidase in patients with hepatic impairment.

Females of Reproductive Potential and Males

There is no FDA guidance on the use of Glucarpidase in women of reproductive potentials and males.

Immunocompromised Patients

There is no FDA guidance one the use of Glucarpidase in patients who are immunocompromised.

Administration and Monitoring

Administration

• Oral

• Intravenous

Monitoring

There is limited information regarding Monitoring of Glucarpidase in the drug label.

• Description

IV Compatibility

There is limited information regarding IV Compatibility of Glucarpidase in the drug label.

Overdosage

Acute Overdose

Signs and Symptoms

• Description

Management

• Description

Chronic Overdose

There is limited information regarding Chronic Overdose of Glucarpidase in the drug label.

Pharmacology

There is limited information regarding Glucarpidase Pharmacology in the drug label.

Mechanism of Action

Structure

File:Glucarpidase01.png

This image is provided by the National Library of Medicine.

Pharmacodynamics

There is limited information regarding Pharmacodynamics of Glucarpidase in the drug label.

Pharmacokinetics

There is limited information regarding Pharmacokinetics of Glucarpidase in the drug label.

Nonclinical Toxicology

There is limited information regarding Nonclinical Toxicology of Glucarpidase in the drug label.

Clinical Studies

There is limited information regarding Clinical Studies of Glucarpidase in the drug label.

How Supplied

Storage

There is limited information regarding Glucarpidase Storage in the drug label.

Images

Drug Images

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Package and Label Display Panel

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Patient Counseling Information

There is limited information regarding Patient Counseling Information of Glucarpidase in the drug label.

Precautions with Alcohol

• Alcohol-Glucarpidase interaction has not been established. Talk to your doctor about the effects of taking alcohol with this medication.

Brand Names

• ®

Look-Alike Drug Names

• A® — B®

Drug Shortage Status

Price

References

The contents of this FDA label are provided by the National Library of Medicine.

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